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Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29–8·24), versus 159 (33%) of 482 patients (95% CI 28·8–37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients). Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. Novartis Pharmaceuticals Corporation.

Background Oral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Customized 3D-printed oral stents offer faster production and achieve comparable patient-reported outcomes to conventionally fabricated stents. However, their design process remains time-consuming, lacks standardization, and relies heavily on skilled technicians. We hypothesized that semi-automating the design process for 3D-printed, mouth-opening, tongue-depressing (MOTD) stents could standardize the design workflow and decrease design time. Methods Using oral stent design principles established over decades by oral oncologists, we created a customized computer program (Autostent) using MATLAB to semi-automate the design process of MOTD stents. We subsequently compared Autostent to a previously described method that utilized non-automated computer-aided design. Three users designed stents for four patients with HNC enrolled in a prospective observational study. These patients were selected based on their varying dental anatomies, and each user repeatedly designed an MOTD stent for each patient three times, employing both the non-automated and semi-automated methods. Both methods were compared in terms of design time and stent volume. Results Semi-automation reduced the average design time by 23.6 min (51.2%, p  = 0.001), regardless of user, dental anatomy, or trial number. Additionally, semi-automation decreased the average stent volume by 4.33 mL (12.9%, p  = 0.016, univariate analysis). Although this reduction was not statistically significant when considering other experimental variables ( p  = 0.40, multivariate analysis), semi-automation did lower the variability in stent volume among users (the overall standard error of the mean decreased by 40%). Conclusion Our semi-automated workflow for designing and fabricating customized, 3D-printed MOTD stents significantly improves efficiency and reduces variability in the design. While these results indicate greater consistency compared to manual methods, further development is warranted to achieve full automation and to optimize clinical integration.

Utilization of biologic skin substitutes for the management of soft tissue defects as an alternative to autologous skin grafts has expanded over the past 2 decades. The purpose of this case series study was to report our experience with Integra® bilayer wound matrix for reconstruction of intraoral oncologic defects. Case records of 6 patients with intraoral oncologic defects reconstructed with Integra® bilayer wound matrix were retrospectively reviewed. The surgical defect location, size, and time to removal of surgical splint varied. Clinically, normal oral epithelialization was noted for all patients. One patient demonstrated a small area of dehiscence and bone exposure after adjuvant radiation therapy which resolved with minimal intervention. Integra bilayer wound matrix is a viable and versatile option for reconstruction of intraoral oncologic surgical defects. Further exploration of wound healing with Integra® matrix, surgical techniques, and cost‐effectiveness is advocated. Integra® bilayer wound matrix is a viable and versatile option for reconstruction of small to large intraoral oncologic surgical defects on movable and nonmoveable mucosa.

Background To evaluate and establish a digital workflow for the custom designing and 3D printing of mouth opening tongue-depressing (MOTD) stents for patients receiving radiotherapy for head and neck cancer. Methods We retrospectively identified 3 patients who received radiation therapy (RT) for primary head and neck cancers with MOTD stents. We compared two methods for obtaining the digital impressions of patients’ teeth. The first method involved segmentation from computed tomography (CT) scans, as previously established by our group, and the second method used 3D scanning of the patients’ articulated stone models that were made during the conventional stent fabrication process. Three independent observers repeated the process to obtain digital impressions which provided data to design customized MOTD stents. For each method, we evaluated the time efficiency, dice similarity coefficient (DSC) for reproducibility, and the 3D printed stents’ accuracy. For the 3D scanning method, we evaluated the registration process using manual and automatic approaches. Results For all patients, the 3D scanning method demonstrated a significant advantage over the CT scanning method in terms of time efficiency with over 60% reduction in time consumed ( p  < 0.0001) and reproducibility with significantly higher DSC ( p  < 0.001). The printed stents were tested over the articulated dental stone models, and the trueness of fit and accuracy of dental anatomy was found to be significantly better for MOTD stents made using the 3D scanning method. The automated registration showed higher accuracy with errors < 0.001 mm compared to manual registration. Conclusions We developed an efficient workflow for custom designing and 3D-printing MOTD radiation stents. This workflow represents a considerable improvement over the CT-derived segmentation method. The application of this rapid and efficient digital workflow into radiation oncology practices can expand the use of these toxicity sparing devices to practices that do not currently have the support to make them.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1 , P  = 4.3 × 10 –7 ; 5p13.2–p13.1, rs16903936, MA = G, EGFLAM , P  = 5.1 × 10 –6 ; 4q21.1, rs10518156, MA = G, SHROOM3 , P  = 7.1 × 10 –6 ; 19q13.42, rs11882068, MA = G, NLRP9 , P  = 1.7 × 10 –5 ; 12q24.33, rs4760542, MA = G, GLT1D1 , P  = 1.8 × 10 –5 ; and 3q27.3, rs11714564, MA = G, RTP1 , P  = 2.9 × 10 –5 . Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826 , a ncRNA class RNA gene, P  = 1.5 × 10 –5 ). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

BackgroundAntiresorptive drugs (ARD) are associated with a known serious adverse event, known as medication-related osteonecrosis of the jaws (MRONJ). Transition from one ARD to another has become common clinical practice with the advent of more potent or safer agents; however, the influence of sequential antiresorptive therapy as a risk factor for MRONJ has not been established.ObjectivesTo investigate the prevalence of MRONJ in oncology or osteoporosis patients treated with two or more sequential ARDs as opposed to a single antiresorptive drug.Material and methodsSystematic electronic literature searches were conducted using Ovid MEDLINE, Ovid EMBASE, and Cochrane Central Register of Controlled Trials. Two review authors retrieved studies using pre-determined eligibility criteria and conducted quality assessment and data extraction. Fixed or random-effects meta-analysis models were used to summarize relative estimates for prevalence of MRONJ.ResultsA total of 483 titles and abstracts were screened, and 18 full texts were retrieved for review. Twelve studies were included in the final qualitative and quantitative synthesis. Random effects meta-analysis models revealed a weighted pooled MRONJ prevalence of 19% (95% CI 10–27%) for sequential pamidronate-zoledronate therapy, 10% (95% CI 3–22%) for sequential ibandronate-zoledronate therapy. Pooled weighted prevalence of MRONJ was 13% (95% CI 3–22%) for sequential bisphosphonate-denosumab therapy while bisphosphonates only was 5% (95% CI 0–9%) and denosumab only was 4% (95% CI 3–5%).ConclusionsThe present systematic review suggests an increased prevalence of MRONJ associated with sequential ARD therapy for pamidronate-zoledronate and bisphosphonate-denosumab administration when compared to single ARD therapy.

Aboriginal residential rehabilitation services in New South Wales provide accommodation and treatment for alcohol and other drug dependence, primarily to Aboriginal Australians. While it is known that many clients arrive at these services with high levels of psychological distress, estimates of how levels of psychological distress change during treatment have been lacking. Latent class growth models were fitted to repeated observations of Kessler’s K10 measure of psychological distress of male clients at four rehabilitation services. K10 trajectories were best described by four trajectory classes, high initial but decreasing distress (Class 1), intermediate initial but decreasing distress (Class 2), mostly high but variable distress (Class 3), and low distress (Class 4). Clients referred from the legal system were more likely to have a K10 trajectory with low or intermediate K10 at admission than clients that self-referred or were referred by family or friends. Clients lacking stable accommodation before admission were more likely to experience a K10 trajectory with high K10 at admission. K10 shows promise as an indicator of well-being for Aboriginal Australians with alcohol or other drug use disorder. More research is required to establish whether trajectories of psychological distress during extended inpatient care for alcohol and other drug dependence may be useful for diagnosing co-occurring psychiatric disorders.

ObjectiveThe purpose of this study was to estimate prevalence/severity of self-reported trismus, determine association with quality of life (QOL), and examine clinical risk factors in a large population of patients treated for oropharyngeal cancer.Materials and methodsA cross-sectional survivorship survey was conducted among patients who completed definitive treatment for oropharyngeal carcinoma, disease-free ≥ 1-year post-treatment (median survival, 7 years among 892 survivors). Associations between trismus and QOL were also analyzed using MDASI-HN, EQ-5D, and MDADI. Dietary and feeding tube status were also correlated to trismus status.ResultsTrismus was self-reported in 31%. Severity of trismus positively correlated (r = 0.29) with higher mean interference scores reflecting a moderate association with quality of life (p < 0.0001). There was a negative correlation for MDADI composite scores (r = − 0.33) indicating increased perceived dysphagia related to trismus severity (p < 0.0001). EQ-5D VAS scores were also negatively correlated with trismus severity (r = − 0.26, p < 0.0001). Larger T-stage (p ≤ 0.001), larger nodal stage (p = 0.03), tumor sub-site (p = 0.05), and concurrent chemoradiation (p = 0.01) associated with increased prevalence of trismus. Diet negatively correlated (r = − 0.27) with trismus severity (p = < 0.0001), and survivors with severe trismus were also more likely to be feeding tube-dependent.ConclusionSeverity of trismus appears to negatively impact quality of life and associate with various adverse functional outcomes in long-term oropharyngeal cancer survivorship. Trismus remains associated with advanced disease stages, tumor sub-site (tonsil), and addition of chemotherapy. Further investigation is merited for the dose-effect relationship to the muscles of mastication.

PurposeThis observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate.MethodsAdults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ.ResultsOverall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5–11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both).ConclusionsThese results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients.

Purpose Many head and neck cancer patients who receive radiation therapy experience radiation-induced dysgeusia (RID), which has no standard treatment. The only supplement controlled clinical trials have evaluated for the treatment of RID is zinc. However, the results of these and other studies investigating the use of zinc for RID have been inconsistent. To assess the validity of zinc as a treatment for RID, we conducted a systematic literature search and performed a meta-analysis to determine the extent to which zinc affects RID incidence and the degree to which ongoing RID responds to zinc. Methods We searched the Ovid MEDLINE, Ovid Embase, PubMed, and Cochrane Library databases to identify studies investigating the use of zinc-based therapy for RID in head and neck cancer patients treated with radiation that were published between January 1, 2003, and November 9, 2017. Using American Society of Clinical Oncology criteria, we selected studies with a high level of evidence for inclusion in the meta-analysis. Results Of the 32 full-text articles eligible for inclusion, three were included in the final review and meta-analysis. The meta-analysis showed that, compared with placebo, zinc reduces the incidence of RID (risk ratio, 0.72; 95% confidence interval, 0.67–0.92) but does not improve taste acuity more rapidly following radiation therapy (risk ratio, 2.58; 95% confidence interval, 0.97–6.88). Conclusion Our findings indicate that zinc-based therapy reduces the incidence of RID but has a minimal effect on ongoing RID. Our findings also highlight the need for additional evidence-based research on this topic.